Mechanisms of Trace Amine-associated Receptor Gene Choice

项目摘要 气味受体（OR）基因表现出一种不寻常的随机单等位基因表达形式，通常 称为单基因或单一表达。在小鼠中，嗅觉感觉神经元表达一个等位基因， 从分散在整个基因组中的> 1，000个基因的大型库中选择一个OR基因。当前型号 OR选择涉及由分布增强子的全基因组网络编排的表观遗传机制。 痕量胺相关受体（TAAR）构成了一个小的嗅觉受体基因家族， 以单数形式表示。然而，TAAR的表观遗传特性在许多方面不同于OR。 关键的方式，质疑是否两者都有一个共同的机制，单一的表达。 该建议的目标是表征TAAR基因的奇异表达机制。我们 已经确定了控制TAAR基因表达的局部增强子，并将利用这一知识来测试 关于这些调节因素如何协调选择的假说。该提案的目的是：（1） 鉴定增强子功能所需的序列基序，2）阐明增强子功能的特异性和空间结构。 增强子功能的程度，以及3）表征TAAR基因的三维相互作用景观 集群这些实验利用TAAR集群的独特方面来测试和扩展当前的模型， 单等位基因表达-一种在无数生物学过程中起关键作用的现象， 剂量补偿、细胞类型特化、表型变异和疾病发病机制。

Project Summary Odorant receptor (OR) genes exhibit an unusual form of random monoallelic expression, commonly referred to as monogenic or singular expression. In the mouse, olfactory sensory neurons express one allele of one OR gene from a large repertoire of >1,000 genes scattered throughout the genome. Current models for OR choice involve epigenetic mechanisms orchestrated by a genome-wide network of distributed enhancers. The Trace Amine Associated Receptors (TAARs) constitute a small olfactory receptor gene family that is also subject to singular expression. However, the epigenetic properties of TAARs differ from ORs in a number of key ways, calling into question whether both share a common mechanism of singular expression. The goal of this proposal is to characterize the mechanisms of singular expression of TAAR genes. We have identified the local enhancers that govern TAAR gene expression and will exploit this knowledge to test hypotheses about how these regulator elements orchestrate choice. The Aims of the proposal are to 1) identify the sequence motifs that are required for enhancer function, 2) elucidate the specificity and spatial extent of enhancer function, and 3) characterize the three-dimensional interaction landscape of the TAAR gene cluster. These experiments exploit unique aspects of the TAAR cluster to test and extend current models of monoallelic expression—a phenomenon that plays a critical role in myriad biological processes including dosage compensation, cell-type specification, phenotypic variation and disease pathogenesis.